Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, USA.
Am J Psychiatry. 2012 Nov;169(11):1150-6. doi: 10.1176/appi.ajp.2012.12040531.
Recent clinical studies have demonstrated that a single subpsychotomimetic dose of ketamine, an ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, produces a rapid antidepressant response in patients with major depressive disorder, with effects lasting up to 2 weeks. Despite enthusiasm about this unexpected efficacy of ketamine, its widespread use as a fast-acting antidepressant in routine clinical settings is curtailed by its abuse potential as well as possible psychotomimetic effects. However, the ability of ketamine to produce a rapid and long-lasting antidepressant response in patients with depression provides a unique opportunity for investigation of mechanisms that mediate these clinically relevant behavioral effects. From a mechanistic perspective, it is easy to imagine how activation of NMDA receptors may trigger cellular and behavioral responses; it is relatively more difficult, however, to envision how transient blockade of one of the key pathways for neuronal communication produces a persistent beneficial effect. The authors discuss recent work linking ketamine's mechanism of action to homeostatic synaptic plasticity processes activated after suppression of NMDA-mediated glutamatergic neurotransmission. They focus on their recent work demonstrating that ketamine-mediated blockade of NMDA receptors at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase, resulting in reduced eEF2 phosphorylation and desuppression of rapid dendritic protein translation, including BDNF (brain-derived neurotrophic factor), which then contributes to synaptic plasticity mechanisms that mediate longterm effects of the drug. The authors also explore possible molecular strategies to target spontaneous neurotransmitter release selectively to help uncover novel presynaptic avenues for the development of fast-acting antidepressants and possibly psychoactive compounds with effectiveness against other neuropsychiatric disorders.
最近的临床研究表明，单次亚精神刺激剂量的氯胺酮，一种离子型谷氨酸能 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂，可在重度抑郁症患者中迅速产生抗抑郁反应，其效果可持续长达 2 周。尽管氯胺酮的这种意外疗效令人兴奋，但由于其滥用潜力以及可能的致幻作用，其作为快速作用的抗抑郁药在常规临床环境中的广泛应用受到限制。然而，氯胺酮能够在抑郁症患者中产生快速而持久的抗抑郁反应，这为研究介导这些临床相关行为效应的机制提供了独特的机会。从机制的角度来看，很容易想象 NMDA 受体的激活如何引发细胞和行为反应；然而，想象一下，NMDA 介导的谷氨酸能神经传递的短暂阻断如何产生持久的有益效应，相对来说就比较困难了。作者讨论了将氯胺酮的作用机制与 NMDA 介导的谷氨酸能神经传递抑制后激活的同源性突触可塑性过程联系起来的最新工作。他们专注于最近的工作，证明氯胺酮在静息状态下对 NMDA 受体的阻断会使真核延伸因子 2（eEF2）激酶失活，导致 eEF2 磷酸化减少和快速树突蛋白翻译的去抑制，包括脑源性神经营养因子（BDNF），这有助于介导药物的长期效应的突触可塑性机制。作者还探讨了可能的分子策略，以选择性地靶向自发性神经递质释放，以帮助揭示快速作用的抗抑郁药和可能对其他神经精神障碍有效的致幻化合物的新的突触前途径。
